Modulation of phospholipase D for the treatment of neurodegenerative disorders

Patent metadata

Field	Value
Publication number	US-9267122-B2
Application number	US-201113305422-A
Country	US
Kind code	B2
Filing date	Nov 28, 2011
Priority date	May 29, 2009
Publication date	Feb 23, 2016
Grant date	Feb 23, 2016

Abstract

The present invention relates to methods of treating neurodegenerative diseases comprising administering, to a subject in need of such treatment, one or more agent that inhibits or reduces the action, including the catalytic activity, of an enzyme of the phospholipase D family, such as phospholipase D1 and/or phospholipase D2. The present invention also relates to cell-based assays which may be used to identify agents that inhibit or reduce the activity of enzymes of the phospholipase D family and that may be used in the treatment of neurodegenerative diseases.

First claim

We claim:

1. A method of treating a neurodegenerative disease selected from the group consisting of Alzheimer's disease, Mild Cognitive Impairment, Parkinson's Disease, Huntington's disease and senile dementia, comprising administering to a subject in need of such treatment, an effective amount of an inhibitor of phospholipase D2, wherein the inhibitor is selected from the group consisting of
i) inhibitors depicted in ( FIG. 11B-M );
(ii) a halopemide derivative comprising a 2-indolyl moiety, a halogenated piperidinylbenzimidazolone moiety and an S-methyl moiety, or a 1,3,8-triazaspiro[4,5]decan-4-one moiety;
(iii) 5-Fluoro-2-indolyl des-chlorohalopemide (“FIPI”);
(iv) N-(2-(4-(2˜oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)ethyl)-2-napthamide;
(v) (1R,2R)—N—((S)-1-(4-(5-bromo-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)propan-2-yl)-2-phenylcyclopropanecarboxamide;
(vi) N-(2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]decan-8-yl)ethyl)quinoline-3-carboxamide; and
(vii) an inhibitor selected from the group consisting of

2. A method of protecting against toxic effects of Aβ42 peptide on a neural cell comprising exposing said cell to an effective amount of an inhibitor of phospholipase D2, wherein the inhibitor is selected from the group consisting of
(i) inhibitors depicted in ( FIG. 11B-M );
(ii) a halopemide derivative comprising a 2-indolyl moiety, a halogenated piperidinyl benzimidazolone moiety and an S-methyl moiety, or a 1,3,8-triazaspiro[4,5]decan-4-one moiety;
(iii) 5-Fluoro-2-indolyl des-chlorohalopemide (“FIPI”);
(iv) N-(2-(4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)ethyl)-2-napthamide;
(v) (1R,2R)—N—((S)-1-(4-(5-bromo-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)propan-2-yl)-2-phenylcyclopropanecarboxamide;
(vi) N-(2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]decan-8-yl)ethyl)quinoline-3-carboxamide; and
(vii) an inhibitor selected from the group consisting of

3. The method of claim 1 where the phospholipase D2 inhibitor is a halopemide derivative comprising a 2-indolyl moiety, a halogenated piperidinyl benzimidazolone moiety and an S-methyl moiety, or a 1,3,8-triazaspiro[4,5]decan-4-one moiety.

4. The method of claim 1 where the phospholipase D2 inhibitor is selected from the group consisting of phospholipase D inhibitors depicted in ( FIG. 11B-M ).

5. The method of claim 1 where the phospholipase D2 inhibitor is 5-Fluoro-2-indolyl des-chlorohalopemide (“FIPI”).

6. The method of claim 1 where the phospholipase D2 inhibitor is N-(2-(4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)ethyl)-2-napthamide.

7. The method of claim 1 where the phospholipase D2 inhibitor is (1R,2R)—N—((S)-1-(4-(5-bromo-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) piperidin-1-yl)propan-2-yl)-2-phenylcyclopropanecarboxamide.

8. The method of claim 1 where the phospholipase D2 inhibitor is N-(2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]decan-8-yl)ethyl)quinoline-3-carboxamide.

Assignees

• Dipaolo Gilbert
• Kim Tae-Wan
• Oliveira Tiago Gil
• Univ Columbia

Inventors

• Dipaolo Gilbert
• Kim Tae-Wan
• Oliveira Tiago Gil

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P39/00

  General protective or antinoxious agents · CPC title

• G01N2405/04

  Phospholipids, i.e. phosphoglycerides · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title